Role of lipid-derived mediators in tumor necrosis factor-induced endothelin-1 release in vivo.
We hypothesized that endothelin (ET) may be released in response to tumor necrosis factor-alpha (TNF) and that platelet-activating factor (PAF) and cyclooxygenase products modulate TNF-induced ET-1 release in vivo. Anesthetized and instrumented pigs were randomly assigned to receive: 1) saline + TNF (n = 8); 2) saline + heat-inactivated TNF (control group, n = 5); 3) WEB 2086 (PAF receptor antagonist) + TNF (n = 7); or 4) indomethacin + TNF (n = 6). Infusion of TNF was associated with increases in mean aortic, mean pulmonary artery, and intratracheal pressures, increases in systemic and pulmonary vascular resistances, and elevated plasma thromboxane B2 concentration. Plasma ET-1 concentrations were unchanged in controls and significantly increased in TNF-treated pigs at 2 to 4 h. WEB 2086 did not modify plasma levels of ET-1 during exogenous infusion of TNF. In contrast, the cyclooxygenase inhibitor, indomethacin, mildly, but not significantly, reduced plasma ET-1 levels. In addition, indomethacin (but not WEB 2086) blocked or attenuated the TNF-induced increases in mean aortic pressure, systemic vascular resistance, mean pulmonary artery pressure, pulmonary vascular resistance, and intratracheal pressure. We conclude that in the pig, cyclooxygenase products modulate some of the cardiovascular responses to TNF and may mildly affect ET-1 biosynthesis. On the other hand, PAF neither significantly influences TNF-induced biosynthesis of ET-1 nor its associated cardiovascular responses.
Kruse-Elliott
K T
KT
Department of Surgical Sciences, University of Wisconsin, Madison 53706, USA.
Whorton
A R
AR
Olson
N C
NC
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D019332:Endothelin-1 / Q000096:biosynthesis / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D008055:Lipids / Q000502:physiology*; D008168:Lung / Q000187:drug effects; D010972:Platelet Activating Factor / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013929:Thromboxane B2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D019332:Endothelin-1; D008055:Lipids; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D013929:Thromboxane B2; D011451:Prostaglandin-Endoperoxide Synthases